Prior studies investigating the interaction between PI3K pathway signaling and AR activity in cell lines and genetically engineered mouse models described a correlation between PTEN loss and resistance to AR-targeted therapy. We are using cell lines, patient derived xenografts, and organoid cultures from PDXs to investigate interactions between PTEN loss and resistance to AR-targeted therapy. We have identified a surprising resistance mechanism that is enhanced in models lacking PTEN, which is predicted to provide resistance to AR-targeted therapy. We are now working on identifying the mechanism whereby this resistance pathway is upregulated and ways to overcome it.